The overall goal of this research plan is to determine whether pharmacological and behavioral interventions stimulate neurogenesis and improve functional recovery after stroke in the adult rat. The persistence of neural stem cells in the adult mammalian brain and evidence that injury stimulates forebrain neurogenesis suggest that endogenous progenitors are a source for neuronal replacement after brain insults or neurodegeneration. We have recently discovered that focal ischemia increases neurogenesis in the adult rat subventricular zone (SVZ). Some SVZ neuroblasts differentiate into neurons in the injured striatum, and these new cells persist for at least 5 weeks after stroke and express phenotypic markers appropriate for neostriatal neurons. Many more neuroblasts that reach the injured striatum, however, fail to survive. Recent work also suggests that behavioral manipulations influence both adult neurogenesis and recovery from stroke, but it is not known whether these processes are linked. The main hypothesis of this proposal is that augmenting neostriatal neurogenesis will improve recovery of sensorimotor function after stroke in the adult rat. The specific hypotheses are: 1) growth/differentiation factors or astrocyte-derived cues will stimulate neurogenesis in the intact SVZ-olfactory bulb pathway, and increase striatal neurogenesis after stroke (Aims 1 and 2); 2) neurogenesis is a major factor in the functional recovery after stroke induced by pharmacological or rehabilitative interventions (Aims 2 and 3); 3) combining growth/differentiation factor treatment and motor training will increase neurogenesis and improve function after stroke more than either treatment alone. (Aim 4). The specific aims are: t) To determine whether specific growthdifferentiation factors or astrocyte-derived cues stimulate the proliferation or differentiation of forebrain SVZ neuroblasts; 2) To determine whether treatment with specific mitogenic and differentiation factors will augment, via striatal neurogenesis, functional recovery after stroke in the adult rat; 3) To investigate whether behavioral interventions to stimulate motor activity in the impaired limbs will enhance neuroblast survival and functional recovery after stroke," and 4) To determine whether combined growthdifferentiation factor treatment and behavioral therapy enhance neurogenesis or fimctional outcome after stroke more than either treatment alone. Progress in these aims will advance our understanding of mechanisms underlying neural stem cell regulation and rehabilitative plasticity after brain injury, and may lead to novel regenerative therapies for stroke.